Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control

Casa, Valentina; Gines, Macarena Moronta; Gusmao, Eduardo Gade; Slotman, Johan A.; Zirkel, Anne; Josipović, Nataša; Oole, Edwin; IJcken, Wilfred F. J. van; Houtsmuller, Adriaan B.; Papantonis, Argyris; Wendt, Kerstin S.

doi:10.1101/gr.253211.119

Cited by 65 publications

(62 citation statements)

References 66 publications

(105 reference statements)

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“…Our results demonstrate that STAG1 and STAG2 display nearly identical distributions across the genome, despite not interacting together in a stable complex. Our finding that the STAG proteins do not physically interact corroborates similar coIP and microscopy results in mESCs and human colorectal cancer lines, and is consistent with a model where cohesin functions as a single ring, rather than as a pair of rings [8,23,25,27,32,41,42]. Several recent reports have found that STAG1 and STAG2 localize at many shared sites, but also localize to a subset of sites exclusively [23][24][25]27].…”

Section: Discussionsupporting

confidence: 91%

“…Our finding that the STAG proteins do not physically interact corroborates similar coIP and microscopy results in mESCs and human colorectal cancer lines, and is consistent with a model where cohesin functions as a single ring, rather than as a pair of rings [8,23,25,27,32,41,42]. Several recent reports have found that STAG1 and STAG2 localize at many shared sites, but also localize to a subset of sites exclusively [23][24][25]27]. However, our analysis in mESCs does not identify a class of sites preferentially occupied by one specific cohesin-STAG complex, and agree with a recent report that shared sites reflect a population average, where some cells have cohesin-STAG1 and others have cohesin-STAG2 at an individual site [25].…”

Section: Discussionsupporting

confidence: 90%

“…Importantly, the SMC1A-STAG interaction was not dependent on DNA or RNA, since the immunoprecipitation was performed in the presence of a nuclease. This result demonstrates that STAG1 and STAG2 proteins do not exist together in a higher-order complex, corroborating a previous study that used both microscopy and Re-ChIP to demonstrate that STAG1 and STAG2 do not colocalize to the same piece of chromatin at the same time [25]. Together with the overlapping pattern of STAG1 and STAG2 localization, our work argues that individual cells within a population have either a cohesin-STAG1 or cohesin-STAG2 complex present at a specific site in the genome at any given time.…”

Section: Overlapping Distribution Of Cohesin-stag1 and Cohesin-stag2supporting

confidence: 91%

“…Recent work has implicated both STAG1 and STAG2 in regulating gene expression and genome organization, however, the molecular basis of STAG-dependent gene regulation has been controversial. Although some studies suggest STAG1 and STAG2 localize to many shared sites across the genome, other studies identify and highlight smaller classes of distinct sites with possibly different functions in various mammalian cell types [23][24][25][26][27]. Some reports have observed that cohesin-STAG1 localizes to CTCF sites and TAD boundaries, whereas cohesin-STAG2 is found at enhancers, promoters, and Polycomb Domains [23,24].…”

Section: Stag1 and Stag2 Are Not Thought To Function Outside Of The Cmentioning

confidence: 99%

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Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells

Arruda

Carico

Justice

et al. 2020

Epigenetics & Chromatin

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Background: The three-dimensional organization of the genome in the nucleus plays an integral role in many biological processes, including gene expression. The genome is folded into DNA loops that bring together distal regulatory elements and genes. Cohesin, a ring-shaped protein complex, is a major player in the formation of DNA loops. Cohesin is composed of a core trimer and one of two variant STAG subunits, STAG1 or STAG2. It is not understood whether variant STAG proteins give rise to cohesin complexes with distinct functions. Recent studies have begun to characterize the roles of STAG1 and STAG2, with partially contradictory results. Results: Here, we generate stable single-knockout embryonic stem cell lines to investigate the individual contributions of STAG1 and STAG2 in regulating cohesin chromosomal localization and function. We report both overlapping roles for STAG1 and STAG2 in cohesin localization and somewhat distinct roles in gene expression. STAG1 and STAG2 occupy the same sites across the genome, yet do not exist together in a higher order complex. Despite their shared localization, STAG1 and STAG2 have both distinct and redundant effects on gene expression. Loss of both STAG1 and STAG2 causes widespread transcriptome dysregulation, altered cohesin DNA occupancy, and reduced cell proliferation. Conclusions: Together, this work reveals the requirement of at least one STAG protein for proper cohesin function. STAG1 and STAG2 have independent roles in cohesin localization and both overlapping and distinct roles in gene expression. The roles of STAG1 and STAG2 in mouse embryonic stem cells may be somewhat different than in other cell types, due to their relative expression levels. These results advance our understanding of the link between mammalian genome organization and gene expression during development and disease contexts.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Overlapping Distribution Of Cohesin-stag1 and Cohesin-stag2supporting

confidence: 91%

Section: Stag1 and Stag2 Are Not Thought To Function Outside Of The Cmentioning

confidence: 99%

See 2 more Smart Citations

Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells

Arruda

Carico

Justice

et al. 2020

Epigenetics & Chromatin

View full text Add to dashboard Cite

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“…We used our previously published ChIP-seq data from two biological replicates of adult mice livers for three proteins that form the cohesin complex: RAD21, STAG1 and STAG2 [55]. RAD21 is necessary for the formation of the core ring of the cohesin complex, which is completed with either STAG1 or STAG2 [56,57]. We defined colocalised events as those where at least two cohesin subunits overlap with CTCF binding.…”

Section: Recently Evolved Tissue-shared Ctcf Binding Efficiently Recrmentioning

confidence: 99%

Functional signatures of evolutionarily young CTCF binding sites

et al. 2020

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Background The introduction of novel CTCF binding sites in gene regulatory regions in the rodent lineage is partly the effect of transposable element expansion, particularly in the murine lineage. The exact mechanism and functional impact of evolutionarily novel CTCF binding sites are not yet fully understood. We investigated the impact of novel subspecies-specific CTCF binding sites in two Mus genus subspecies, Mus musculus domesticus and Mus musculus castaneus, that diverged 0.5 million years ago. Results CTCF binding site evolution is influenced by the action of the B2-B4 family of transposable elements independently in both lineages, leading to the proliferation of novel CTCF binding sites. A subset of evolutionarily young sites may harbour transcriptional functionality as evidenced by the stability of their binding across multiple tissues in M. musculus domesticus (BL6), while overall the distance of subspecies-specific CTCF binding to the nearest transcription start sites and/or topologically associated domains (TADs) is largely similar to musculus-common CTCF sites. Remarkably, we discovered a recurrent regulatory architecture consisting of a CTCF binding site and an interferon gene that appears to have been tandemly duplicated to create a 15-gene cluster on chromosome 4, thus forming a novel BL6 specific immune locus in which CTCF may play a regulatory role. Conclusions Our results demonstrate that thousands of CTCF binding sites show multiple functional signatures rapidly after incorporation into the genome.

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A cohesin‐associated gene score may predict immune checkpoint blockade in hepatocellular carcinoma

Liu

Chen

et al. 2022

FEBS Open Bio

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Stromal antigen 1 (STAG1), a component of cohesion, is overexpressed in various cancers, but it is unclear whether it has a role in the transcriptional regulation of hepatocellular carcinoma (HCC). To test this hypothesis, here, we screened global HCC datasets and performed multiscale embedded gene co-expression network analysis to identify the potential functional modules of differentially expressed STAG1 co-expressed genes. The putative transcriptional targets of STAG1 were identified using chromatin immunoprecipitation followed by high-throughput DNA sequencing. The cohesin-associated gene score (CAGS) was quantified using the The Cancer Genome Atlas HCC cohort and single-sample gene set enrichment analysis. Distinct cohesin-associated gene patterns were identified by calculating the euclidean distance of each patient. We assessed the potential ability of the CAGS in predicting immune checkpoint blockade (ICB) treatment response using IMvigor210 and GSE78220 cohorts. STAG1 was upregulated in 3313 HCC tissue samples compared with 2692 normal liver tissue samples (standard mean difference = 0.54). A total of three cohesinassociated gene patterns were identified, where cluster 2 had a high TP53 mutated rate and a poor survival outcome. Low CAGS predicted a significant survival advantage but presaged poor immunotherapy response. Differentially expressed STAG1 co-expression genes were enriched in the mitotic cell cycle, lymphocyte activation, and blood vessel development. PDS5A and PDGFRA were predicted as the downstream transcriptional targets of STAG1. In summary, STAG1 is significantly upregulated in global HCC tissue samples and may participate in blood vessel development and the mitotic cell cycle. A cohesin-associated gene scoring system may have potential to predict the ICB response.Abbreviations CAG, cohesin-associated gene; CAGS, cohesin-associated genes scores; ChIP-seq, chromatin immunoprecipitation sequencing; CIBERSORT, cell type identification by estimating relative subsets of RNA transcripts; CR, complete remission; ESTIMATE, estimation of STromal and immune cells in MAlignant tumor tissue using expression data; HCC, hepatocellular carcinoma; ICB, immune checkpoint blockade; MEGENA, multiscale embedded gene co-expression network analysis; PD, progressive disease; PR, partial remission; SD, stable disease; SMD, standard mean difference; ssGSEA, single-sample gene set enrichment analysis; STAG1, stromal antigen 1; WGCNA, weighted gene co-expression network analysis.

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Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control

Cited by 65 publications

References 66 publications

Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells

Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells

Functional signatures of evolutionarily young CTCF binding sites

A cohesin‐associated gene score may predict immune checkpoint blockade in hepatocellular carcinoma

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